Use this site to develop the concepts surrounding anticonvulsant drugs and their mechanism of action.

Group 2: Lillian, Christine, Albert, & Megan

Anticonvulsant Drugs

Anticonvulsant drugs are used to control sometimes violent involuntary muscle contractions and diffferent types of seizures: grand-mal seizures or tonic-clonic, simple partial seizures, and secondary partial seizures.

The following are drugs used to help control these convulsions and are sometimes accompanied by epileptic attacks:

Carbamazepine (Tegretol)

• Highly effective against grand-mal and partial seizures.
• Indicated for treatment of trigeminal neuralgia.
• Also effective for othter neuroopathic pains: glossopharyngial neuralgia, postherpetic neuralgia, and diabetic neuropathy.
• Dental Use: Pain relief for trigeminal or glossopharyngial neuralgia.
• Unlabeled or investigational use: Treatment of resistant schizophrenia, ethanol withdrawal, restless leg syndrome, and post-traumatic stress disorders.
• Pharmacologic Effects: Binds to inactivated Na+ channels and slowing neuronal recovery from activation.
  • Also reduces Ca++ and Na+ flux across the neuronal membrane.
  • Absorbed slowly; distributed throughout the body with its highest concentration occuring in the liver, kidneys, and brain.
• Adverse Effects:
  • Cardiovascular: Arrythmias, bradycardia, CHF, hypertension, hypotension, syncope, thromboemoblism, thrombophlebitis.
  • CNS: Amnesia, confusion, depression, dizziness, fatigue, headache, slurred speech.
  • Dermatologic: Alopecia, alterations in skin pigmentation, erythema mutiforme, exfoliative dermatitiis, Steven's-Johnson syndrom, urticaria.
  • Gastrointestinal: Abdominal pain, anorexia, constipation, diarrhea, nausea, pancreatitiis, vomiting, xerostomia.
  • Genito-urinary: Renal failure, urinary frequency, urinary retention, impotence.
  • Hematogic: Agranulocytosis, aplastic anemia, bone marrow suppression, eosinophilia, leukocytosis, leukopenia, thrombocytopenia.
  • Hepatic: Hepatic failure, hepatitis, jaundice.
  • Ocular: Blurred vision, conjuctivitis, lens opacities, nystagmus.

Anticonvulsants

• Anticonvulsants control but do not cure epilepsy.
• The primary objective of anticonvusant therapy is to supress seizures while causing minimal impairment of CNS function.
• Drugs are described as having characteristics spectra for treating the various forms of seizures.
• Prescribing antiepileptic drugs for conditions outside their spectra may lead to problems beyond simple therapeutic failure.
  • For example: Absence seizures can be exacerbated by many of the drugs used to treat tonic-clonic seizures.
• Broad spectrum drugs include: Valproate, lamotrigine, benzodiazepines, and acetazolamide.
• Drugs used to treat Tonic-clonic and partial seizures include: Phenytoin and phenoarbital (most common).
• Adverse reactions include: Sedation (most common), gingival overgrowth, aplastic anemia, hepatotoxicity, renal stones, visual disturbances and fevers.
• When saturated, converts to zero-order kinetics and the drug level increases.

There are several classes of drugs that have anticonvulsant properties:

Aldehydes

• Paraldehyde: One of the earliest anticonvulsants. Still used to treat status epilepticus, particularly where there are no resuscitation facilities.

Aromatic allylic alcohols

• Stiripentol: Indicated for the treatment of severe myoclonic epilepsy in infancy (SMEI).

Barbiturates

• Act on the central nervous system (CNS) as depressants, and by virtue of this they produce a wide spectrum of effects, from mild sedation to anesthesia.
• Mechanism of action: is to inhibit and thus interfering with the transmission of impulses from the thalamus to the cortex of the brain.
• Used as a hypnotic in short-term treatment of insomnia, reduce anxiety, provide sedation preoperatively, and management of epilepsy.
• The following are classified as anticonvulsants:
  • Phenobarbital.
  • Methylphenobarbital: Known as mephobarbital in the US. No longer marketed in the UK
  • Metharbitalz; No longer marketed in the UK or US.
  • Barbexaclone: Only available in some European countries.

Benzodiazepines

• Have hypnotic, anxiolytic, anticonvulsive, amnestic and muscle relaxant properties.
• They act as a CNS depressant and the relative strength of each of these properties each drug varies.
• Long-term use can be problematic due to the development of tolerance to the anticonvulsant effects and dependency.
• Of the many drugs in this class, only a few are used to treat epilepsy:
  • Clobazam: Notably used on a short-term basis around menstruation in women with catamenial epilepsy.
  • Clonazepam.
  • Clorazepate.
• The following benzodiazepines are used to treat status epilepticus:
  • Diazepam: Can be given rectally by trained care-givers.
  • Midazolam: Increasingly being used as an alternative to diazepam. It is rapidly absorbed by the buccal mucosa.
  • Lorazepam: Given by injection in hospital.Nitrazepam, temazepam, and especially nimetazepam are powerful anticonvulsant agents, however their use is rare due to an increased incidence of side effects and strong sedative and motor-impairing properties.
• Mechanism of Action: Enhancement of the inhibitory effect of GABA resulting by increased neuronalll membrane permeability to chloride ions. This shift in chloride ions results in hyperpolarization and stabilization; thus, a decrease in anxiety.

Bromides

• Potassium bromide: The earliest effective treatment for epilepsy.

Carbamates

• Felbamate: Has a rare but life-threatening side effects.

Carboxamides

• Carbamazepine: A popular anticonvulsant that is available in generic formulations.
• Oxcarbazepine: A derivative of carbamazepine that has similar efficacy but is better tolerated and is also available generically.
• Eslicarbazepine acetate

Fatty acids

• The valproates — valproic acid, sodium valproate, and divalproex sodium
• Vigabatrin
• Progabide
• Tiagabine
• Vigabatrin and progabide are also analogs of GABA.

Fructose derivatives

• Topiramate

Gaba analogs

• Gabapentin
• Pregabalin

Hydantoins

• Ethotoin
• Mephenytoin
• Fosphenytoin
• Mechanism of action: Phenytoin works by stabilizing neuronal membranes and decreasing seizure activity by increasing efflux or decreasing influx of sodium ions across cell membranes in the motor cortex during generation of nerve impulses. Thus, it also inhibits the spread of seizure activity in the moto cortex.
• Use: Used for the control of generalized convulsive status epilepticus (seizures that last longer than 5 minutes). It is also use for tonic-clonic seizures or grand mal seizures, and psychomotor seizures. Used as prevention and treatment of seizures occuring during neurosurgery.
• Adverse Effects: 1.) Hypotension. 2.) Nystagmus. 3.) dizziness, drowsiness. 4.) paresthesia. 5.) headacheache. 6.) confusion, 7.) gingival hyperplasia. 8.) ataxia.

Oxazolidinediones

- Paramethadione
- Trimethadione
- Ethadione

Propionates

- Beclamide

Pyrimidinediones

- Primidone

Pyrrolidines

- Brivaracetam
- Levetiracetam
- Seletracetam

Succinimides

- Ethosuximide (Zarontin)(1955).
- Phensuximide (Milontin)
- Methsuxmide (Celontin)

Mechanism of action: 1.) Increases the seizure thrteshold. 2.) Suppreses paroxysmal spike-and-wave pattern in absence seizures or petit mal. 3.) Depresses nerve transmission in the motor cortex.

Use: Management of absence or petit mal seizures.

Adverse Effects: Urticaria, Steven-Johnson's syndrome, Agranulocytosis, eosinophilia, leukoplenia, pancytopenia, myopia, nausea, vomiting.

Sulfonamides

- Acetazolamide
- Sultiame
- Methazolamide
- Zonisamide

Triazines

- Lamotrigine

Ureas

- Pheneturide
- Phenacemide

Valproylamides (amide derivatives of valproate)

- Valpromide
- Valnoctamide

Epilepsy is a group of disorders that involve a chronic stereotyped recurrent attack of involuntary behavior or experience or changes in neurologic function caused by electrical activity in the brain that can be recorded via an EEG. The episode is called a seizure. Partial seizures are divided int simple or complex attacks. Most generalized seizures are tonic-clonic and absence seizures. Absence seizures are also called petit mal. Symptoms include a brief (only a few seconds) loss of consciousness with characteristic EEG waves and little movement. Usually begin in childhood and then later disappear middle age and the patient is generally unaware that these seizures and occurring. Tonic-clonic seizures are also called grand mal and include longer periods of loss of consciousness and major motor activity of the large muscles of the body. The seizure starts with the body becoming rigid and the patient falling to the floor. Tonic rigidity is followed by clonic jerking of the face, limbs, or tongue. Lastly the patient becomes limp and comatose. The patient will gradually return to a conscious state. When the patient awakens confusion, headache, and drowsiness will be present. Partial (focal) epilepsies involve activation of only part of the brain, and the location of the activity determines the clinical manifestations. When consciousness is not impaired, the attack is called simple partial seizure. When consciousness is impaired, the attack is termed a complex partial attack. In some patients these seizures will have an aura, and full consciousness is slow to return.